Rise 'n Die, HIV: Strategies for a Cure Based on Waking the AIDS Virus

Rousing the human immunodeficiency virus (HIV) from slumber may not sound like a good idea. But just as it is next to impossible to lure and trap a hibernating animal, catching a virus on the move is far easier than snaring one lying dormant.

That's the thinking behind some strategies to effectively eradicate latent reservoirs of HIV—thought to be the virus's last stand when under attack from increasingly effective drug cocktails. Researchers are uncovering multiple methods for awakening and subsequently destroying the virus, which hides out in "resting" immune cells. But they are far from agreeing on which approach offers the most realistic hope—or just how much hope to have in the seemingly unattainable goal to cure AIDS. "This is a very optimistic and maybe even impossible objective," says Douglas Richman, the director of the Center for AIDS Research at the University of California, San Diego. "But it is our number-one objective now."

Drug cocktails—or more technically, highly active antiretroviral treatment (HAART)—have turned what used to be a death sentence into more of a chronic disease in recent years. But an HIV-positive diagnosis still generally means a shorter, sicker life and one that necessitates a continuous supply of expensive therapies; no therapy today can completely eliminate the virus from the body.

"Whenever anybody stops HAART, the virus comes back," says Robert Siliciano, who studies the dynamics of HIV replication at the Howard Hughes Medical Institute and Johns Hopkins University School of Medicine.

Hiding out in CD4 cells
HIV's resting place is the immune system's memory CD4 T cells, which have the ability to recognize foreign bacteria and viruses from previous encounters. (From the second meeting on, they replicate and mount an attack.) In these cells, the virus can sit quietly for years, even decades, remaining unseen by the immune system and antiretrovirals. "Since immunologic memory is for life," says Richman, "then so is maintenance for latent HIV."

But once CD4 cells awaken to an invader, HIV rears its head, too, and begins to replicate with its host. So researchers are now on the hunt for a way either to ensure that deactivation is permanent for any CD4 cell harboring HIV, or to spark activation for all infected CD4 cells—with anti-HIV drugs ready and waiting to attack.

Most experts favor the second strategy, aiming to awaken and attack the virus repeatedly. "If you do this enough times, and deplete the pool of latently infected cells, you could potentially cure patients from infection," says Eric Verdin, a senior investigator at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco.

Chemical wake-up call
Many factors appear to restrict replication of the HIV virus in latent cells, and Verdin's team described last month in PLoS Pathogens one such mechanism: methylation, a chemical modification of DNA that reduces gene activity. They also identified a drug, 5-aza-2'deoxycytidine, that inhibited this restriction process and caused HIV to reactivate and replicate. Alternatively, researchers can target histone deacetylases (HDACs), key enzymes that work with DNA methylation; blocking HDACs also ultimately wakes HIV.

But inhibiting methylation or HDACs alone may not be enough, according to Verdin. A major problem is toxicity: impeding either may not only activate latent virus, but also a whole lot of other cellular genes leading to symptoms like those seen in the side effects of cancer chemotherapy. Another big obstacle is that just one viral recluse is enough to refill the reservoir.

The key, then, is a compound that targets only the "safe haven" cells. One potential drug is prostratin, a compound isolated from a Samoan medicinal plant that revs up CD4 cell division. Prostratin is more effective when used with both HDAC inhibitors and with 5-aza-2'deoxycytidine. This synergy allows the drugs to be used at lower concentrations, thereby reducing toxicity, and could "increase the chances that only the virus is reactivated," Verdin says. He explains that HDACs, methylation and prostratin regulate different sets of genes; only those genes under the control of all three would fully awaken. "There are incredible synergies between the classes of drugs," he says. "This is the wave of the future."

Toxicities are unlikely to be completely eliminated but, as Siliciano suggests, researchers could start looking at eradication strategies similar to cancer chemotherapy and "accept a fair amount of toxicity." A new study in Nature Medicine by a team of Canadian and U.S. researchers actually describes a cancerlike therapy using targeted chemotherapy, along with HAART to attack both the viruses circulating in the body and those playing hide-and-seek. (Scientific American is part of the Nature Publishing Group.)
A long way to go before trials
Even if researchers find a reasonably safe drug candidate, clinical trials could be difficult given that the only way to truly determine if eradication is complete is to take a patient off HAART—a potentially dangerous and unethical risk. This quandary has inspired some researchers to add macaques as test subjects, although those animals are not void of drawbacks, either. "One has to collect a lot of cells to measure the latent reservoir," Richman says, noting that fewer than one cell in a million is latently infected. "That's a challenge in a big human, but an even greater challenge in a much smaller monkey."

As if these obstacles were not enough, latent CD4 cells may not even be the only hideout for HIV. "One should never underestimate one's enemy," Richman warns, noting other places the virus could theoretically hide, including macrophages or stem cells.

At this point, the research is still aimed at understanding the mechanisms. Richman predicts that any therapy that could rouse all the HIV in a patient's body and successfully eliminate it is still a decade or two away. "It's still a bit of a dream," he says, "but one has to be an optimist in this business."